Parenteral solutions containing 7-halo-1,2,3,4-tetrahydro-3-aryl-6-quinazoline sulfonamides

ABSTRACT

Disclosed herein are parenteral solutions containing 7-halo-1,2,3, 4-tetrahydro-3-aryl-6-quinazoline sulfonamide in Tris or Bis-Tris or Tris buffer useful in the treatment of hypertension, heart disease and heart failure and renal disease. Also disclosed are methods for preparing such solutions.

This is a continuation of application Ser. No. 08/387,477, filed Feb. 13, 1995, now U.S. Pat. No. 5,633,240 which is a continuation in part of application Ser. No. 08/299,493 filed Sep. 1, 1994 now U.S. Pat. No. 5,684,009.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to parenteral solutions containing 7-Halo-1,2,3,4-tetrahydro-3-aryl-6-qinazoline sulfonamide.

2. Description of the Related Art

Metolazone is a quinazoline diuretic approved for use in an oral tablet form (MYKROX®) for the treatment of hypertension, alone or in combination with other anti-hypertensive drugs of a different class. This compound acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excluded in approximately equivalent amounts. The increased delivery of sodium to the distal-tubular exchange site results in increased potassium excretion.

To treat hypertension, the compound may be administered in oral dosage forms such as in the form of a tablet containing from 0.5-10 mg of metolazone, or it may be administered in the form of an intravenous solution.

Metolazone is also indicated for use in treating heart failure and renal disease. Further, when metolazone is combined with furosemide (lasix), the effectiveness of the diuretics is greatly enhanced. Furosemide can be administered intravenously to obtain the best and most rapid effect in emergencies. However, there is no intravenous formulation available of metolazone since metolazone is sparingly soluble in most solvents. Metolazone is only sparingly soluble in water, but is said to be somewhat more soluble in plasma, blood, alkali and organic solvents.

U.S. Pat. Nos. 3,360,518 and 3,557,111 disclose methods for preparing metolazone.

DESCRIPTION OF THE INVENTION

The present invention provides parenteral solutions comprising as an active ingredient a 7-Halo-1,2,3,4-tetrahydro-3-aryl-6-quinazoline sulfonamide of the following formula: ##STR1## wherein X is a halogen; R₁, R₂, R₃ and R₄ are independently selected from hydrogen and alkyl groups having from about 1 to 6 carbon atoms; and R₅ is hydrogen or an alkyl group having from about 1 to 6 carbon atoms.

More specifically, the present invention provides parenteral solutions suitable for intravenous administration containing as an active ingredient an effective anti-hypertensive amount of 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(-2-methylphenyl)-4-oxo-6-quinazoline sulfonamide (metolazone) in a sterile solvent comprising a bis-(2-hydroxyethyl)-amino!tris-(hydroxymethyl)methane (Bis-Tris) buffer having a pH from about 10.5 to 12.5, and preferably from 11.5 to 12, i.e., metolazone-Bis-Tris solutions.

The invention further provides parenteral solutions suitable for intravenous administration containing Metolazone as an active ingredient in a sterile solvent comprising a Tris-(hydroxymethyl) amino methane, hydrochloride (Tris) buffer having a pH of from about 10.5 to 12.5, and preferably from about 11.5-12, i.e., metolazone-tris solutions.

The invention further provides solutions having extended stability that are suitable for parenteral administration comprising metolazone in a Bis-Tris or Tris buffer having a pH of from about 11.5 to 12.

Also included within the scope of the invention are methods for producing such solutions.

Still further, the invention provides solutions suitable for parenteral, e.g., intravenous, administration comprising an effective anti-hypertensive amount of metolazone in a Bis-Tris or Tris buffer having a pH of from about 11.5 to 12.

Yet further, the invention provides solutions suitable for parenteral administration comprising furosemide and metolazone in Bis-Tris or Tris buffer at a pH of from about 11.5 to about 12.

Further, the invention provides methods for treating an anti-hypertensive patient which comprises parenteral, e.g., intravenous, administration of an effective amount of a solution of metolazone in a Bis-Tris buffer.

The invention also encompasses methods for treating patients suffering from or affected by edema or edematious states comprising parenteral, e.g., intravenous, administration of an effective amount of a solution of metolazone in Tris buffer. Representative edematious states include, for example, congestive heart failure and hypertension.

Parenteral solutions comprising metolazone in Bis-Tris or Tris buffer according to the invention are typically prepared by mixing the required amount of metolazone, which may be purified prior to use, is mixed with the buffer and adding to the resulting solution sodium hydroxide or other suitable base until a pH of about 12 to 12.5 is reached. To this highly basic solution is then added a protic acid, such as, for example, acetic acid, preferably about 1 molar acetic acid, to adjust the pH of the solution to that at which metolazone is completely soluble. The process is preferably carried out at room temperature, although other temperatures are acceptable.

Most preferred solutions of metolazone and Bis-Tris or Tris buffer contain about 1 mg of metolazone per ml of solution. The concentration of Bis-Tris or Tris buffer in the solution is typically about 0.05M. The resulting solutions after cooling to room temperature may be sterilized by known means, e.g., ultra-filtration preferably a 13 mm, 0.45 micron filter, terminal autoclave heating, or ethylene oxide treatment and may be packaged into vials suitable for dispensing as parenteral products.

The preparation thus obtained at a pH of about 11.5 to 12 was found, quite unexpectedly, to remain in solution. The metolazone/Bis-Tris and metolazone/Tris aqueous formulations demonstrate remarkable stability when stored at room temperature over at least a three week period without the formation of turbidity or precipitate.

The solutions thus formulated are indicated for the treatment of hypertension, heart failure, or renal disease. Solutions may also be prepared in a similar manner to contain furosemide and metolazone. As with any potent drug, the dosage must be individualized by the treating clinician.

One skilled in the art will recognize that modifications may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illustrated further by the following examples which are not to be construed as limiting the invention or scope of the specific procedures described herein.

EXAMPLE 1

To a mixture containing indicated quantities of metolazone (Research Biochemicals Inc., Lot # CC-1088E), cyclodextrin (American Maize Products Co.), and with or without polyvinyl pyrrolidones (Sigma Chemical Co.), in differing amounts, as well as a quantity (as indicated) of different buffers at different concentrations, were added. This mixture was stirred, and 5N NaOH solution was added dropwise until a clear solution resulted. The pH of this solution was generally between 12.0-12.5. (It was allowed to stand at room temperature for 30 minutes in cases where cyclodextrins were used). To this solution, 1M acetic acid was added in order to adjust to the desired pH at which the metolazone was completely soluble. The solution was filtered through 13 mm, 0.45 micron filter and stored in vials at room temperature and 40° C. for several days. The results of these experiments are reported below in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     METOLAZONE SOLUBILITY                                                          Buffer Used        Final pH  Observations on stability                         (0.1M unless                                                                           Final conc. Metolazone                                                                    of   Temp. for                                                                           after standing for period of time                 otherwise stated)                                                                      mg/ml      Solution                                                                            Storage                                                                             24 hr                                                                             48 hr                                                                               72 hr                                                                               96 hr                                                                             1 Wk                                                                              2 Wk                                                                              3 Wk                        __________________________________________________________________________     12 ml Na                                                                               1          6.7  RT   ppt                                               Acetate +                                                                      0.1 ml Tween                                                                   80                                                                             12 ml Na                                                                               1          9.0  RT   ppt                                               Acetate +                                                                      0.1 ml Tween                                                                   80                                                                             12 ml Na                                                                               1          6    RT   ppt                                               Acetate +                                                                      0.2 ml Tween                                                                   80                                                                             12 ml Na                                                                               1          6    RT   ppt                                               Acetate +                                                                      0.5 ml Tween                                                                   80                                                                             12 ml Na                                                                               1          9.5  RT   ppt                                               Acetate +                                                                      2 ml Tween                                                                     80                                                                             12 ml Na                                                                               1          10.0 RT   ppt                                               Acetate +                                                                      3 ml Tween                                                                     80                                                                             12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml AMPSO.sup.1                                                               12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml Bicine.sup.2                                                              12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml Bis-Tris                                                                  12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml CAPS.sup.3                                                                12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml CHES.sup.4                                                                12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml Glycine                                                                   12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml TAPS.sup.5                                                                12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml Tricine                                                                   12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml TEA                                                                       12 ml Na                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Acetate +                                                                      2 ml Tris                                                                      5% NaHCO.sub.3                                                                           1.5      11   RT   ppt                                               AMPSO   2          9.5  RT   ppt                                               AMPSO   2          10.0 RT   ppt                                               AMPSO   2          10.5 RT   ppt                                               AMPSO   1          10.0 RT   ppt                                               AMPSO   1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             ppt                                            AMPSO     1.0      12.0 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            AMPSO     1.0      12.0 40° C.                                                                       ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            AMPSO     2.0      11.5 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            AMPSO     2.0      11.5 40° C.                                                                       ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            AMPSO     2.0      12.0 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            AMPSO     2.0      12.0 40° C.                                                                       ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            Bicine  2          9.5  RT   ppt                                               Bicine  2          10.0 RT   ppt                                               Bicine  2          10.5 RT   ppt                                               Bicine  1          10.0 RT   ppt                                               Bicine  1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Bicine 0.05                                                                            1          11.5 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                               Bicine 0.05                                                                            1          11.5 40° C.                                                                       ppt                                               Bicine 0.05                                                                            1          12.0 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                               Bicine 0.05                                                                            1          12.0 40° C.                                                                       ppt                                               Bicine 0.05                                                                            2          11.5 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            Bicine 0.05                                                                            2          11.5 40° C.                                                                       ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            Bicine 0.05                                                                            2          12.0 RT   ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            Bicine 0.05                                                                            2          12.0 40° C.                                                                       ppt                                                                               ppt  ppt  ppt                                                                               ppt                                                                               ppt                            Bis-Tris                                                                                 1.5      10.4 RT   ppt                                               Bis-Tris                                                                               2          9.5  RT   ppt                                               Bis-Tris                                                                               2          10.0 RT   ppt                                               Bis-Tris                                                                               2          10.5 RT   ppt                                               Bis-Tris                                                                               1          10.0 RT   ppt                                               Bis-Tris                                                                               1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Bis-Tris                                                                                 1.0      11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             Clear                       0.05M                                                                          Bis-Tris                                                                                 1.0      11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             Clear                       0.05M                                                                          Bis-Tris                                                                                 1.0      12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             Clear                       0.05M                                                                          Bis-Tris                                                                                 1.0      12.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             Clear                       0.05M                                                                          Bis-Tris                                                                                 2.0      11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            0.05M                                                                          Bis-Tris                                                                                 2.0      11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            0.05M                                                                          Bis-Tris                                                                                 2.0      12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            0.05M                                                                          Bis-Tris                                                                                 2.0      12.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            0.05M                                                                          CAPS    2          9.5  RT   ppt                                               CAPS    2          10.0 RT   ppt                                               CAPS    2          10.5 RT   ppt                                               CAPS    1          10.0 RT   ppt                                               CAPS    1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       CAPS      1.5      11   RT   ppt                                               CAPS      1.5      10.4 RT   ppt                                               CAPS 0.05                                                                                1.0      11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               CAPS 0.05                                                                                1.0      11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            CAPS 0.05                                                                                1.0      12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             ppt                         CAPS 0.05                                                                                1.0      12.0 40° C.                                                                       Clear                                                                             ppt                                            CAPS 0.05                                                                                2.0      11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            CAPS 0.05                                                                                2.0      11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            CAPS 0.05                                                                                2.0      12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            CAPS 0.05                                                                                2.0      12.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            CHES    1          11.2 RT   ppt                                               CHES    1          10.8 RT   ppt                                               CHES    1          10.3 RT   ppt                                               CHES      1.5      10.4 RT   ppt                                               CHES in D5W                                                                            2          9.5  RT   ppt                                               CHES in D5W                                                                            2          10.0 RT   ppt                                               CHES in D5W                                                                            2          10.5 RT   ppt                                               CHES in D5W                                                                            1          10.0 RT   ppt                                               CHES in D5W                                                                            1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       CHES in D5W                                                                            1          9.3  RT   ppt                                               CHES in D5W                                                                            1          11.5 RT   Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            1          11.5 40° C.                                                                       Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            1          12.0 RT   Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            1          12.0 40° C.                                                                       Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            2          11.5 RT   Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            2          11.5 40° C.                                                                       Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            2          12.0 RT   Clear                                                                             ppt                                            0.05                                                                           CHES in D5W                                                                            2          12.0 40° C.                                                                       Clear                                                                             ppt                                            0.05                                                                           Glycine 1          11.3 RT   ppt                                               Glycine 1          10.9 RT   ppt                                               Glycine 1          10.3 RT   ppt                                               Glycine   1.5      10.4 RT   ppt                                               Glycine 2          9.5  RT   ppt                                               Glycine 2          10.0 RT   ppt                                               Glycine 2          10.5 RT   ppt                                               Glycine 1          10.0 RT   ppt                                               Glycine 1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       H.sub.2 O                                                                              1          10.5 RT   Clear                                                                             Clear                                                                               Color/ppt                                 H.sub.2 O                                                                              1          10.5 40° C.                                                                       Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              1          11.0 RT   Clear                                                                             Clear                                                                               Color/ppt                                 H.sub.2 O                                                                              1          11.0 40° C.                                                                       Clear                                                                             ppt                                            H.sub.2 O                                                                              2          10.5 RT   Clear                                                                             Color                                          H.sub.2 O                                                                              2          10.5 40° C.                                                                       Clear                                                                             ppt                                            H.sub.2 O                                                                              2          11.0 RT   Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              2          11.0 40° C.                                                                       Clear                                                                             ppt                                            H.sub.2 O                                                                              1          11.0 RT   Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              1          11.0 40° C.                                                                       Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              1          10.5 RT   Clear                                                                             Color                                          H.sub.2 O                                                                              1          10.5 40° C.                                                                       Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              2          10.5 RT   Clear                                                                             Color/ppt                                      H.sub.2 O                                                                              2          10.5 40° C.                                                                       Clear                                                                             Color                                          H.sub.2 O                                                                              2          11.0 RT   Clear                                                                             Color                                          H.sub.2 O                                                                              2          11.0 40° C.                                                                       Clear                                                                             Color                                          K-Phosphate                                                                              1.5      11   RT   ppt                                               1.0M                                                                           Na Acetate                                                                             1          9.3  RT   ppt                                               Buffer in D5W                                                                  Na Acetate                                                                             2          9.5  RT   ppt                                               Buffer                                                                         Na Acetate                                                                             2          10.0 RT   ppt                                               Buffer                                                                         Na Acetate                                                                             2          10.5 RT   ppt                                               Buffer                                                                         Na Acetate                                                                             1          10.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1          10.0 RT   ppt                                               Buffer                                                                         Na Acetate                                                                             1          9.5  RT   ppt                                               Buffer                                                                         Na Acetate                                                                             1          10.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1          10.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1.0 with 88 mg β CD                                                                  11   RT   Clear                                                                             Clear                                                                               ppt                                       Buffer                                                                         Na Acetate                                                                             1.0 with 88 mg                                                                            11   RT   Clear                                                                             ppt  ppt                                       Buffer  Encapcine                                                              Na Acetate                                                                             1.0 with 88 mg β CD                                                                  11   RT   Clear                                                                             ppt  ppt                                       Buffer                                                                         Na Acetate                                                                             1.0 with 88 mg γ-CD                                                                 11   RT   Clear                                                                             ppt                                            Buffer                                                                         Na Acetate                                                                             1.0 with 176 mg γ-CD                                                                9.8  RT   Clear                                                                             Clear                                                                               ppt                                       Buffer                                                                         Na Acetate                                                                             1.0 with 440 mg γ-CD                                                                9.8  RT   Clear                                                                             ppt                                            Buffer                                                                         Na Acetate                                                                             1.0 with 44 mg β-CD                                                                  10.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1.0 with 44 mg β CD                                                                  10.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             1.0 with 66 mg β CD                                                                  10.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             ppt                               Buffer                                                                         Na Acetate                                                                             3          3.4  RT   ppt                                               Buffer 95%                                                                     ETOH(3:1)                                                                      Na Acetate                                                                               1.5      11   RT   ppt                                               Buffer                                                                         Na Acetate                                                                             1.0 with 30 mg                                                                            9.5  RT   ppt                                                       PVP(MW 40,000) Int                                                             Visc 26-35                                                             Na Acetate                                                                             1.0 with 30 mg                                                                            9.5  RT   ppt                                                       PVP(MW 40,000) Int                                                             Visc 28-32                                                             Na Acetate                                                                             1.0 with 30 mg                                                                            9.5  RT   ppt                                                       PVP(MW 10,000) Int                                                             Visc 12-18                                                             Na Acetate                                                                             1.0 with 5 mg PCP                                                                         9.5  RT   ppt                                                       (MW 40,000) Int Visc                                                           26-35                                                                  Na Acetate                                                                             1.0 with 5 mg PVP                                                                         9.5  RT   ppt                                                       (MW 40,000) Int Visc                                                           28-32                                                                  Na Acetate                                                                             1.0 with 5 mg PVP                                                                         9.5  RT   ppt                                                       (MW 10,000) Int Visc                                                           12-18                                                                  Saline  1          10.5 RT   Clear                                                                             Clear                                                                               Color                                     Saline  1          10.5 40° C.                                                                       Clear                                                                             ppt                                            Saline  1          11.0 RT   Clear                                                                             Color                                          Saline  1          11.0 40° C.                                                                       Clear                                                                             ppt                                            Saline  2          10.5 RT   Clear                                                                             Color                                          Saline  2          10.5 40° C.                                                                       Clear                                                                             ppt                                            Saline  2          11.0 RT   Clear                                                                             Clear                                                                               ppt                                       Saline  2          11.0 40° C.                                                                       Clear                                                                             ppt                                            Saline  1          11.0 RT   Clear                                                                             Color                                          Saline  1          11.0 40° C.                                                                       Clear                                                                             Color                                          TAPS    2          9.5  RT   ppt                                               TAPS    2          10.0 RT   ppt                                               TAPS    2          10.5 RT   ppt                                               TAPS    1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       TAPS 0.05                                                                              1          10.0 RT   ppt                                               TAPS 0.05                                                                              1          11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            TAPS 0.05                                                                              1          11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            TAPS 0.05                                                                              1          12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            TAPS 0.05                                                                              1          12.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            TAPS 0.05                                                                              2          11.5 RT   Clear                                                                             ppt                                            TAPS 0.05                                                                              2          11.5 40° C.                                                                       Clear                                                                             ppt                                            TAPS 0.05                                                                              2          12.0 RT   Clear                                                                             ppt                                            TAPS 0.05                                                                              2          12.0 40° C.                                                                       Clear                                                                             ppt                                            TEA     >1         10.5 RT   ppt                                               TEA     >1         10.5 40° C.                                                                       ppt                                               TEA     >1         11.0 RT   ppt                                               TEA     >1         11.0 40° C.                                                                       ppt                                               TEA     >1         11.5 RT   ppt                                               TEA     >1         11.5 40° C.                                                                       ppt                                               TEA     1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       TEA + 1.8%                                                                             >1         10.5 RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             >1         11.0 RT   ppt                                               NaCl(1;1)                                                                      TEA + 1.8%                                                                             >1         11.5 RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          9.5  RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          10.0 RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          10.5 RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             1          10.0 RT   ppt                                               NaCl(1:1)                                                                      TEA + 1.8%                                                                             1          11.5 RT   Clear                                                                             Clear                                                                               ppt                                       NaCl(1:1)                                                                      TEA + 1.8%                                                                             1          11.5 40° C.                                                                       Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             1          12.0 RT   Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             1          12.0 40° C.                                                                       Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          11.5 RT   Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          11.5 40° C.                                                                       Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          12.0 RT   Clear                                                                             ppt                                            NaCl(1:1)                                                                      TEA + 1.8%                                                                             2          12.0 40° C.                                                                       Clear                                                                             ppt                                            NaCl(1:1)                                                                      Tricine.sup.6                                                                          1          11.3 RT   ppt                                               Tricine 1          11.0 RT   ppt                                               Tricine 1          10.4 RT   ppt                                               Tricine   1.5      10.4 RT   ppt                                               Tricine 2          9.5  RT   ppt                                               Tricine 2          10.0 RT   ppt                                               Tricine 2          10.5 RT   ppt                                               Tricine 1          10.0 RT   ppt                                               Tricine 1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       Tricine 0.05                                                                           1          11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             ppt                         Tricine 0.05                                                                           1          11.5 40° C.                                                                       Clear                                                                             ppt                                            Tricine 0.05                                                                           1          12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             Clear                                                                             ppt                         Tricine 0.05                                                                           1          12.0 40° C.                                                                       Clear                                                                             ppt                                            Tricine 0.05                                                                             2.0      11.5 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            Tricine 0.05                                                                             2.0      11.5 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            Tricine 0.05                                                                             2.0      12.0 RT   Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            Tricine 0.05                                                                             2.0      12.0 40° C.                                                                       Clear                                                                             Clear                                                                               Clear                                                                               Clear                                                                             Clear                                                                             ppt                            TEA     1          11.3 RT   ppt                                               TEA     1          10.9 RT   ppt                                               TEA     1          10.6 RT   ppt                                               TEA     2          9.5  RT   ppt                                               TEA     2          10.0 RT   ppt                                               TEA     2          10.5 RT   ppt                                               TEA     1          10.0 RT   ppt                                               TEA       1.5      10.4 RT   ppt                                               Tris      1.5      10.4 RT   ppt                                               Tris      1.5      7.5  RT   ppt                                               Tris      1.5      10.4 RT   ppt                                               Tris      1.5      10.1 RT   ppt                                               Tris    2          10.8 RT   ppt                                               Tris    5          11.2 RT   ppt                                               Tris     10        12   RT   ppt                                               Tris    2          9.5  RT   ppt                                               Tris    2          10.0 RT   ppt                                               Tris    2          10.5 RT   ppt                                               Tris    1          10.0 RT   ppt                                               Tris    1.0 with 66 mg β CD                                                                  10.0 RT   Clear                                                                             Clear                                                                               ppt                                       __________________________________________________________________________      .sup.1 3 (1,1dimethyl-2-hydroxyethyl)amino2-hydroxypropanesulfonic acid.       .sup.2 N,Nbis-(2-hydroxyethyl)glycine                                          .sup.3 3(cyclohexylamino)propanesulfonic acid                                  .sup.4 2(cyclohexylamino)ethanesulfonic acid                                   .sup.5 3( trishydroxymethyl)methyl!amino)propanesulfonic acid                  .sup.6 N trishydroxymethyl)methyl!glycine                                

                                      TABLE 2                                      __________________________________________________________________________     METOLAZONE SOLUBILITY                                                          Buffer Used                                                                            Final conc.                                                                          Final pH                                                         (0.1M unless                                                                           Metolazone                                                                           of   Temp. for                  On-                              otherwise stated)                                                                      mg/ml Solution                                                                            Storage                                                                             24 hr                                                                             48 hr                                                                             72 hr                                                                             96 hr                                                                             1 Wk                                                                              3 Wk                                                                              10 Wks                                                                             going                            __________________________________________________________________________     *Tris 0.05                                                                             1     11.5 RT   Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     11.5 40° C.                                                                       Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     12.0 RT   Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     12.0 40° C.                                                                       Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     11.5 RT   Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     11.5 40° C.                                                                       Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     12.0 RT   Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            *Tris 0.05                                                                             1     12.0 40° C.                                                                       Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                             Clear                                                                              Clear                            __________________________________________________________________________      GRAPH CODES                                                                    RT = Room Temperature                                                          CD = Cyclodextrin                                                              PVP = Polyvinylpyrrolidone                                                     TEA = Triethanolamine                                                          *Solutions remained colorless unless indicated otherwise                 

As the above data demonstrates, Metolazone is unexpectedly stable as a formulation in 0.05M Bis-Tris at pHs from about 11.5 to 12.0 and as a formulation in 0.05M Tris at pHs from about 11.5 to 12.0.

The activity of metolazone dissolved in the buffer systems of the invention is demonstrated by the following examples. In examples 2-4 below rats are deprived of food and water. After 24 hours, water only (25 ml/kg) is given orally and a solution of the drug, i.e., lasix or metolazone, is given intraperitoneally. Urine is collected during the following 24 hours. The results of each example are shown in the accompanying table.

EXAMPLE 2

Metolazone Rat Experiment

Rats 450 gms received 2 mg/kg Metolazone intraperitoneally in tris buffer. Group I Control received Tris containing no metolazone, Group II (rats originally used in saline control experiments) received 1 ml of a solution containing 1 mg/ml (2 mg/kg dose) metolazone in 0.05M Tris at pH 11.5 to 12. Group III were animals (not previously treated) receiving 1 ml of a solution of 1 mg/ml (2 mg/kg dose) in Tris buffer metolazone. The volume of urine produced by the rats is shown below in Table III.

                  TABLE III                                                        ______________________________________                                         Diuretic Effect of Metolazone (IP route in Rats                                (Values indicate amount (ml) of urine collected)                                                               Group III                                                       Group II       IP Metolazone                                       Group I     IP Metolazone 2 mg/kg                                                                         2 mg/kg                                             IP Tris     1 ml (1 mg/ml) in Tris                                                                        1 ml (1 mg/ml) in                              Rat  buffer (1 ml)                                                                              buffer (Rats from                                                                             Tris buffer                                    No.  (Control Group)                                                                            control group used)                                                                           (different rats used)                          ______________________________________                                         1     8          16             22                                             2     7          15             15                                             3     9          17             15                                             4    10          18             12                                             5    10          17             13                                             Mean 9 ± 1    17 ± 1**    16 ± 3**                                    ± SD                                                                        ______________________________________                                          **Results from Goups II and III when compared to control Group I, were         significantly different (p < 0.01)                                       

EXAMPLE 3

Lasox Rat Experiment

Sprague-Dawley rats, 450-500g, received saline or furosemide (Lasix) in normal saline intraperitoneally at the concentrations listed below in a 1 ml volume. The volume of urine produced by the animals is shown in Table 2.

Group I (5 rats) was administered 1 ml of normal saline intraperitoneally. Group II (5 rats) was originally used in saline controls) administered 1 ml of a 2 mg/ml Lasix/saline solution intraperitoneally (4 mg/kg dose).

Group III (5 previously untreated rats) was administered 1 ml of a 2 mg/ml Lasix/saline solution intraperitoneally (4 mg/kg dose). Group IV (5 previously untreated rats) was administered 1 ml of a 1 mg/ml Lasix/saline solution intraperitoneally (2 mg/kg dose). This diuretic effect of these formulations is shown below in Table IV.

                                      TABLE IV                                     __________________________________________________________________________     Diuretic Effect of Furosemide (Lasix) in Rats (IP route)                       (Values indicate amount (ml) of urine collected)                                               Group II Group III                                                                              Group IV                                                      IP Lasix 4 mg/kg                                                                        IP Lasix 4 mg/kg                                                                       IP Lasix 2 mg/kg                                    Group I   1 ml (2 mg/ml) in                                                                       1 ml (2 mg/ml) in                                                                      1 ml (1 mg/ml) in                                   IP Normal saline                                                                         normal saline (Rats                                                                     normal saline                                                                          normal saline                                       (1 ml) (Control                                                                          from control                                                                            (previously                                                                            (previously                                   Rat No.                                                                              group)    group used)                                                                             untreated rats)                                                                        untreated rats)                               __________________________________________________________________________     1     3         17       16      10                                            2     2         15       17      10                                            3     3         17       13      7                                             4     2         19       12      8                                             5     3         19       13      9                                             Avg. ± SD                                                                         3 ± 0.5                                                                               17 ± 2**                                                                             14 ± 2**                                                                            9 ± 1**                                    __________________________________________________________________________      **P results from Groups II, III, and IV when compared to control Group I,      were significantly different (p < 0.01).                                 

EXAMPLE 4

Diuretic Effects of Metolazone/Lasix Combination Therapy

Rats (450 g previously untreated) were intraperitoneally administered 0.5 ml of 4 mg/ml lasix solution (4 mg/kg dose) and 0.5 ml of 2 mg/ml metolazone/tris buffer solution, pH 11.5, (2 mg/kg dose). The results are shown in Table V below.

                  TABLE V                                                          ______________________________________                                         Diuretic effect of Furosemide (Lasix)                                          and Metolazone (IV route) combination therapy.                                              Group (n = 5)                                                                  IP lasix 4 mg/kg, 0.5 ml (4 mg/ml) in                                          normal saline and IP metolazone 2 mg/kg,                                       0.5 mg (2 mg/ml) in Tris Buffer. (Rats                                         employed that did not previously receive                                       therapy)                                                          Rat No.      Volume of Urine Collected (ml)                                    ______________________________________                                         1            22                                                                2            22                                                                3            20                                                                4            20                                                                5            22                                                                mean ± SD 21 ± 1                                                         ______________________________________                                    

The results of these examples demonstrate that metalozone and lasix have distinctive action, increasing urine output. When lasix and metalozone are used in combination therapy the action is synergistic with more diuretic effect than with either drug alone.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. 

What is claimed is:
 1. A solution suitable for parenteral administration comprising an anti-hypertensive of a compound of the formula ##STR2## wherein X is halogen; R₁, R₂, R₃, R₄ are independently selected from hydrogen and alkyl having from 1 to 6 carbon atoms; andR₅ is hydrogen or alkyl having from 1 to 6 carbon atoms, dissolved in an aqueous Bis-Tris buffer system having a pH of from about 10.5 to 12.5.
 2. A solution suitable for parenteral administration according to claim 1 wherein the quinazoline sulfonamide is metolazone.
 3. A solution according to claim 2 which comprises from about 0.01 to 1 mg per ml of metolazone in about 0.05M to about 0.5M Bis-Tis buffer solution having a pH of about 11.5 to
 12. 4. A method for the treatment of a patient suffering from hypertension which comprises the intravenous administration of an effective amount of a solution according to claim
 2. 5. A method for the treatment of a patient suffering from edema states which comprises the intravenous administration of a solution according to claim
 3. 6. A method for the preparation of a solution according to claim 2 which comprises forming a mixture of metolazone and Bis-Tris buffer at a pH of about 10.5 to 12.5.
 7. A solution comprising an effective diuretic amount of a mixture of furosemide and metolazone in Bis-Tris buffer at a pH of from about 11.5 to
 12. 8. A solution suitable for parenteral administration comprising an anti-hypertensive of a compound of the formula ##STR3## wherein X is halogen; R₁, R₂, R₃, R₄ are independently selected from hydrogen and alkyl having from 1 to 6 carbon atoms; andR₅ is hydrogen or alkyl having from 1 to 6 carbon atoms, dissolved in an aqueous Tris buffer system having a pH of from about 10.5 to 12.5.
 9. A solution suitable for parenteral administration according to claim 8 wherein the quinazoline sulfonamide is metolazone.
 10. A solution according to claim 9 which comprises from about 0.01 to 1 mg per ml of metolazone in about 0.05M to about 0.5M Tris buffer solution having a pH of about 11.5 to
 12. 11. A method for the treatment of a patient suffering from hypertension, congestive heart failure or other edematious states which comprises the intravenous administration of an effective amount of a solution according to claim
 9. 12. A method for the treatment of a patient suffering from edema which comprises the intravenous administration of a solution according to claim
 10. 13. A method for the preparation of a solution according to claim 9 which comprises forming a mixture of metolazone and Tris buffer at a pH of about 10.5 to 12.5. 